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Research Article Open Access

Augmenting Subarachnoid Block Analgesia in Caesarean Section Delivery

with Sub-Psychotomimetic Dose of Ketamine
Rotimi Adegbenga Owolabi1*, Oluwole Isaac Adeyemi2 and Sunday Elisha Oyelere3
1Department of Medical Pharmacology and Therapeutics, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
2Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
3Department of Anaesthesia, Mother and Child Hospital, Ondo, Nigeria
*Corresponding author: Rotimi Adegbenga Owolabi, Department of Medical Pharmacology and Therapeutics, College of Health Sciences, Obafemi Awolowo
University, Ile-Ife, Nigeria, Tel: +2348122287226; E-mail: rolabi07@yahoo.com
Received date: July 25, 2018; Accepted date: August 14, 2018; Published date: August 21, 2018
Copyright: ©2018 Owolabi RA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

This study investigated the effect of low sub-psychotomimetic dose (0.3 mg/kg) of ketamine on subarachnoid
block-induced analgesia with a view to assessing the analgesic effectiveness of combination of low dose ketamine
with subarachnoid block in management of post caesarean section pain.

Spinal anaesthesia was performed in 120 healthy pregnant women scheduled for elective caesarean delivery
using 10 mg hyperbaric bupivacaine. Parturient mothers were randomly selected into four groups (n=30) consisting
of K1, K2, NK1 and NK2. K1 received 0.3 mg/kg intravenous ketamine diluted with sterile water for injection to 5 mL,
as a bolus dose 2 min before surgical incision; K2 was treated as K1 but at 2 minutes after delivery of baby, while
NK1 and NK2 received equivalent volumes of normal saline 2 min before surgical incision and 2 min after baby
extraction respectively. Age, weight, duration of surgery (DOS) and the time of first request for analgesia (TFA) for all
participants were recorded. Post-operative pain intensity was assessed using a visual analogue scale (VASPI) at 2,
4, 8, 12, 24 and 36 h after spinal anaesthesia induction. Results were analyzed using ANOVA and Kruskal-Wallis
tests. Student Newman-Keuls and Man-Whitney rank sum tests were used for post hoc analysis as appropriate. P
value<0.05 was considered statistically significant.

There was no significant difference in age and weight across groups, but duration of surgery was statistically
prolonged in K1 group relative to NK1 group. Low dose ketamine significantly augmented the analgesic effect of
spinal block anaesthesia, especially when given at two minutes before surgical incision.

Keywords: Ketamine; Bupivacaine;
Caesarean section
Introduction
Millions of caesarean deliveries are performed globally on daily
basis, many of which are due to indications ranging from emergency
situations (e.g. foetal distress) to maternal request [1]. However,
despite a growing trend in acute pain management, there still exist
deficiencies in post-operative pain management, and participants
continue to receive inadequate care of algesia post-operatively. Post-
operative pain following caesarean section often leads to both
physiological and psychological consequences; including inability of
the mother to give adequate care to the neonate immediately after
birth. Benefits of adequate post-operative analgesia include early
mobilization and less hospital stay, reduced morbidity, reduced risk of
deep vein thrombosis, reduced hospital costs and increased participant
satisfaction.
Ketamine, a dissociative anaesthetic agent commonly used for
minor surgical procedures in many developing countries has been
reported to have analgesic properties [2-4]. The widespread use of
ketamine has been limited by the psychotomimetic side effects it
produces at moderate doses [5]. Although previous studies have
reported the analgesic potential of low dose ketamine [6,7], the
Analgesia; Spinal block; relevance of time of administration during the peri-operative period
and the time profile of the augmented analgesia produced by low dose
ketamine have not been extensively assessed.
This study set out to determine whether intravenous ketamine, at a
dose of 0.3 mg/kg, would be effective for improving post-operative
analgesia after caesarean section under subarachnoid block and
examines the time profile of the resulting analgesia at different
moments during the peri-operative period.
Materials and Methods
This study was undertaken as a prospective, placebo-controlled,
double-blind, randomized study using 120 parturient mothers. Ethical
approval was obtained from the Ethical Research Committees of the
Obafemi Awolowo University, Ile-Ife, Nigeria and Mother and Child
Hospital, Ondo, Nigeria. Informed consent was obtained from each
participant whose physical status belonged to class ≤ II according to
the American Society of Anesthesiology (ASA) physical status, and
was scheduled for elective caesarean section.
The criteria for exclusion in this study included parturient mothers
with known cardiac disease, gestational hypertension (>Class II in
American Society of Anaesthesiologists (ASA) Classification of
Physical Health Status), epilepsy, psychiatric disorder, and bleeding
disorders. Others are parturient mothers with multiple gestations,

J Anesth Clin Res, an open access journal Volume 9 • Issue 8 • 1000853

ISSN:2155-6148
Citation: Owolabi RA, Adeyemi OI, Oyelere SE (2018) Augmenting Subarachnoid Block Analgesia in Caesarean Section Delivery with Sub-
Psychotomimetic Dose of Ketamine. J Anesth Clin Res 9: 853. doi:10.4172/2155-6148.1000853
parity greater than one, previous caesarean section, history of allergy
to ketamine and heavy bupivacaine and evidence of foetal compromise
or distress.
Each parturient mother was reviewed by the investigator the night
before the scheduled surgery (preoperative assessment) during which
every participant was trained on the use of a 10 cm Visual Analogue
Scale for scoring pain intensity (VASPI) [8]. No pre-medication was
given to any of the participants. All participants for the study received
the same intravenous fluid preload of 20 ml/kg normal saline over
10-15 min via an 18-G intravenous cannula sited in the non-dominant
hand before receiving spinal anaesthesia at a sitting position.
The parturient mothers were divided into 4 groups of 30 each by
simple randomization technique of consecutive numbers. The four
groups consisted of K1, K2, NK1 and NK2. All groups received heavy
bupivacaine 10 mg injected over 30 sec into the subarachnoid space
after confirming correct placement of the spinal needle in the L3-L4
inter-space. Thereafter, each participant had caesarean section under
spinal anaesthesia, using the standard technique of surgery-
Pfannenstiel incision, extraction of baby, exteriorization of the uterus
and repair of layers.
Group K1 received 0.3 mg/kg ketamine [9,10] as a bolus dose
intravenously 2 min before surgical incision (after subarachnoid
block); K2 received 0.3 mg/kg ketamine as a bolus dose via the vein 2
min after delivery of baby, while groups NK1 and NK2 received
equivalent volumes of intravenous normal saline 2 min before surgical
incision, and 2 min after delivery of baby respectively. The post-
operative pain intensity experienced by the participant, assessed based
on the participant’s feedback on the Visual Analogue Scale was taken at
2, 4, 8, 12, 24 and 36 h after spinal anaesthesia was instituted [11-13].
Data was obtained using a designed data collection proforma form.
Data collected was analyzed using Primer of Biostatistics by Stanton A.
Glantz, Version 3.01. Results were analyzed using ANOVA and
Kruskal-Wallis tests. Student Newman-Keuls and Man-Whitney rank
sum tests were used for post hoc analysis. P value<0.05 was considered
statistically significant.
Results
Demographic characteristics of the study groups
ANOVA statistics showed no significant difference (p=0.420) in
mean maternal age and mean maternal weights (p=0.262) across the all
groups in this study (Table 1).
Demographic Characteristics of the Study Groups
K1 (n=30) K2 (n=30) NK1 (n=30) NK2 ANOVA
(n=30) p-value
Age 29.97 ± 28.77 ± 29.97 ± 4.97 31.33 ± 0.42
(years) 5.78 5.56 7.09
Weight 73.20 ± 72.33 ± 75.57 ± 7.96 75.23 ± 0.262
(kg) 7.17 8.19 6.06
Table 1: Demographic characteristics of the study groups.
Values expressed in mean ± SEM. No statistical difference across all
groups (ANOVA). K1 received 0.3 mg/kg ketamine as a bolus dose
intravenously 2 min before surgical incision (after subarachnoid
block); K2 received 0.3 mg/kg ketamine as a bolus dose via the vein 2
J Anesth Clin Res, an open access journal
ISSN:2155-6148
Page 2 of 5
min after delivery of baby, while groups NK1 and NK2 received
equivalent volumes of intravenous normal saline 2 min before surgical
incision, and 2 min after delivery of baby respectively.
Effect of low dose intravenous ketamine (0.3 mg/kg) on
duration of surgery and time of first request for analgesia
One-Way ANOVA revealed significant difference (F(29,119)=2.92;
p=0.035) in the means of duration of surgery across the groups. The
post-hoc analysis revealed that surgery duration in group K1 was
significantly longer than NK1 (p=0.033) while there was no significant
difference when the following groups were compared: K1/K2, p=0.936;
K1/NK2, p=0.926; K2/NK1, p=0.134; K2/NK2, p=1.000; and NK1/
NK2, p=0.143 (Table 2).
Similarly, there was significant difference in of TFA (F(29,119)=69.5;
p<0.0001) across the groups (Table 2). The post-hoc analysis revealed
that TFA was significantly smaller in group NK1 compared with group
K1; TFA was significantly smaller in group NK2 compared with K2;
TFA was significantly smaller in group K2 compared with K1 (Table 2).
Duration of Surgery and Time of First Request for Analgesia
K1 (n=30) K2 (n=30) NK1 NK2 ANOVA
(n=30) (n=30) p-value
DOS 46.83 ± 45.60 ± 41.0 ± 45.53 ± 0.035
(mins) 8.06 7.18 10.40* 6.44
TFA (mins) 204.2 ± 164.4 ± 99.0 ± 112.4 ± <0.0001
42.6 33.3* 24.8* 22.9#
Table 2: Effect of low dose intravenous ketamine (0.3 mg/kg) on time
of first request for analgesia and duration of surgery.
Values are expressed in Mean ± SEM. *=p<0.05 relative to K1,
#=p<0.05 relative to K2, Duration of Surgery (DOS), Time of First
Request for Analgesia (TFA). K1 received 0.3 mg/kg ketamine as a
bolus dose intravenously 2 min before surgical incision (after
subarachnoid block); K2 received 0.3 mg/kg ketamine as a bolus dose
via the vein 2 min after delivery of baby, while groups NK1 and NK2
received equivalent volumes of intravenous normal saline 2 min before
surgical incision, and 2 min after delivery of baby respectively.
Effect of intravenous low dose ketamine (0.3 mg/kg) on post-
caesarean section pain intensity following subarachnoid
block using visual analogue score
Krusal-Wallis statistics revealed significantly (p<0.05) lower visual
analogue score of pain intensity (VASPI) in the combined ketamine
group (K1+K2) when compared with the combined non-ketamine
group (NK1+NK2) at all assessment points within 36 h after spinal
anaesthesia (Figure 1a). Similarly, there was significantly (p<0.05)
lower VASPI in K1 relative to NK1 at all points of assessment (Figure
1c). The VASPI was lower in K1 group relative to K2 group at 4, 8, 12
and 36 h, though the difference did not get to a level of significance
(Figure 1b), but the pain intensity at the points of assessment was
significantly lower in K2 when compared with NK2 except at the 12th h
mark where the difference was not statistically significant (Figure 1d).
Values are expressed in Mean ± SEM. *=p<0.05 relative to non-
ketamine group. Visual Analogue Score (VAS) n=30. Ketamine group
comprised K1+K2 (K1 received 0.3 mg/kg ketamine as a bolus dose
intravenously 2 min before surgical incision (after subarachnoid
Volume 9 • Issue 8 • 1000853
Citation: Owolabi RA, Adeyemi OI, Oyelere SE (2018) Augmenting Subarachnoid Block Analgesia in Caesarean Section Delivery with Sub-
Psychotomimetic Dose of Ketamine. J Anesth Clin Res 9: 853. doi:10.4172/2155-6148.1000853

Page 3 of 5

block); K2 received 0.3 mg/kg ketamine as a bolus dose via the vein 2
min after delivery of baby). Non-ketamine comprised NK1+NK2 (NK1
and NK2 received equivalent volumes of intravenous normal saline 2
min before surgical incision, and 2 min after delivery of baby
respectively).

Figure 1c: Effect of intravenous low dose ketamine (0.3 mg/kg) on

post-caesarean section pain intensity following subarachnoid block
Figure 1a: Effect of intravenous low dose ketamine (0.3 mg/kg) on using visual analogue score.
post-caesarean section pain intensity following subarachnoid block
using visual analogue score.

Figure 1b: Effect of intravenous low dose ketamine (0.3 mg/kg) on

post-caesarean section pain intensity following subarachnoid block
using visual analogue score.
Values are expressed in Mean ± SEM. No significant difference
between the groups throughout post-surgery duration of observation
36 h Visual Analogue Score (VAS). n=30, K1 received 0.3 mg/kg
ketamine as a bolus dose intravenously 2 min before surgical incision,
K2 received 0.3 mg/kg ketamine as a bolus dose via the vein 2 min
after delivery of baby.
Values are expressed in Mean ± SEM. *=p<0.05 relative to NK1
group. Visual Analogue Score (VAS). n=30. K1 received 0.3 mg/kg
ketamine as a bolus dose intravenously 2 min before surgical incision
(after subarachnoid block); NK1 received saline as a bolus dose
intravenously 2 min before surgical incision.
Values are expressed in Mean ± SEM. *= p<0.05 relative to NK2
group. Visual Analogue Score (VAS). n=30. K2 group received 0.3
mg/kg ketamine as a bolus dose intravenously 2 min after baby
extraction while NK2 group received saline as a bolus dose
intravenously 2 min after baby extraction.
Figure 1d: Effect of intravenous low dose ketamine (0.3 mg/kg) on
post-caesarean section pain intensity following subarachnoid block
using visual analogue score.
Discussion
Nowadays, satisfactory post-operative pain control is one of the
most important as-yet unresolved challenges in the surgical setting and
has a major impact on patients and on the health system in general
[14]. Ketamine is a well-established drug that has been in use for
around 50 years [15] and is increasingly more consolidated in modern
clinical practice [14]. It produces a spectrum of biological effects
summed up as dissociative anaesthesia which comprises hypnosis,
psychotomimetic effects, sedation and unconsciousness at higher
doses; intense analgesia (or more accurately anti-nociception);
increased sympathetic activity; and maintenance of airway tone and
respiration [16]. The widespread use of analgesic effect of ketamine has
been limited because of various side effects including psychotomimetic
at moderate doses [17]. Hence this study explored the effect of a low-

J Anesth Clin Res, an open access journal Volume 9 • Issue 8 • 1000853

ISSN:2155-6148
Citation: Owolabi RA, Adeyemi OI, Oyelere SE (2018) Augmenting Subarachnoid Block Analgesia in Caesarean Section Delivery with Sub-
Psychotomimetic Dose of Ketamine. J Anesth Clin Res 9: 853. doi:10.4172/2155-6148.1000853
dose ketamine, earlier reported to be devoid of psychotomimetic
effects in preclinical and clinical studies [18-20], on analgesia of
subarachnoid anaesthesia in post caesarean section mothers.
Findings of this study indicated that the participants were
comparable in age and weight. Previous studies reported the influence
of age and weight on perception of pain in humans [21,22] hence the
possible bias of age and weight on perception of pain is ruled out in
this study.
The significant increase in the time to first request for analgesia
(TFA) in the ketamine groups relative to the non-ketamine groups and
the significant reduction in the visual analogue score of pain intensity
(VASPI) at all assessment points for the ketamine groups relative to the
corresponding non-ketamine groups are suggestive of significant
enhancement of analgesia by low-dose ketamine administration. This
is also supported by the absence of any significant change in TFA and
VASPI when NK1 was compared with NK2. These are consistent with
previous findings of significant delay in the time for first request for
analgesics in participants who had intravenous low dose ketamine
peri-operatively relative to participants who did not [7,23].
Administration of low-dose ketamine 2 min (K1) before incision
produced significant delay in TFA when compared with
administration of same drug at the same dose 2 min after the birth of
baby (K2). Similarly, VASPI scores for the K1 group at 4. 8, 12 and 36 h
are lower when compared to K2, albeit the difference was not
statistically significant. Altogether, these findings point to
augmentation of analgesia following administration of low-dose
ketamine preoperatively, and the pre-incision administration of low-
dose ketamine produced better enhancement of analgesia than that
produced by administration after birth of baby. Moreover, the
enhanced analgesia lasted for the whole period of observation 36 h in
this study.
The analgesic enhancement reported for ketamine in this study can
be explained by the pharmacological properties of this drug. NMDA
receptor has been reported to play an important role in the
sensitization of peripheral nociceptive receptors and conduction of
nociceptive impulses in the central nervous system [2]. It is generally
considered that ketamine-induced supraspinal blockade of the NR2B
NMDA sub-unit has the most important anti-nociceptive influence
[24], however ketamine is also reputed for acting to augment opioid
mu-receptor function [25-27], albeit its analgesia has been reported
not to be reduced by naloxone; which negates a primary opioid-
mediated mechanism of action. In support of the non-opioid
mechanisms of analgesia hypothesis, recent studies have suggested that
ketamine analgesia seems to be largely associated with increased
dopamine activity in mice. Ketamine also augments endogenous anti-
nociceptive systems–presumably, in part, via its aminergic
(serotonergic and noradrenergic) activation and inhibition of re-
uptake [28]. The activation of the aminergic systems have also been
widely reported for classical and novel antidepressants. Hence, another
plausible explanation of ketamine-induced potentiation of analgesia as
reported in this study is a corollary of its antidepressant effect [29-31]
which is rapid in development and endures well after the drug has
been eliminated (more than 36 h after administration in this study),
judging from the T1/2 of ketamine [32]. Pain and depression have
been reported to be often closely linked [33], although the direction of
the causative relationship between the two is less clear. This association
is often explored in the use of antidepressants in pain management.
Alternatively, ketamine may set in chain of cell signaling cascades that
interrupt the gradual propagation of pathophysiological changes
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Page 4 of 5
associated with pain mediation [34]. As outlined in previous studies,
ketamine regulates a number of gene expression pathways potentially
linked to pain mediation, including NMDA receptor expression,
astrocytic activation and synaptic structure and function. Of course all
of these different systems do not act in isolation, but are themselves
part of the integrated nervous system with a myriad of interactions
occurring at all levels [34], ultimately resulting in inhibition of pain
mediation by low dose ketamine as reported in this study.
Conclusion
In view of these findings of this study, which are suggestive that low-
dose ketamine is a valuable adjuvant in perioperative management of
pain in women undergoing caesarean section, it is recommended that
the safety on this drug at the dose employed in this study be assessed
on maternal and foetal well-being in the peri and postoperative
periods.
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Psychotomimetic Dose of Ketamine. J Anesth Clin Res 9: 853. doi:10.4172/2155-6148.1000853
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